I. Field of Invention
The present invention relates generally to the fields of oncology and cancer therapy. In some aspects, the present invention concerns combination therapies including oncolytic viruses such as adenoviruses and immune modulating therapies. In other aspects, the present invention concerns the measurement or detection of biomarkers that distinguish responders from non-responders to oncolytic viral therapy.
II. Background
It is estimated that 43,800 new cases of primary brain tumor, both malignant and nonmalignant, were diagnosed in the U.S. in 2005. It was estimated at 20,500 primary malignant brain tumors including astrocytic (42%) were expected in 2007. This was a more male predominant disease with estimated 11,700 in men and 8,800 in women in 2007. There were approximately 12,700 people who died with brain disease from these tumors estimated in the US in 2007. These tumors account for 1.4% of all adult cancers and 22% of all childhood cancers. This accounts for 2.4% of all cancer related deaths (SEER Cancer Statistics Review).
Onocolytic viruses have shown potential as anti-cancer agents. Genetic modification of the viruses to selectively replicate in cancer cells further increases their efficacy. In gliomas, for example, three kinds of viruses have been shown to be useful in animal models: reoviruses that can replicate selectively in tumors with an activated ras pathway (Coffey et al., 1998); genetically altered herpes simplex viruses (Martuza et al., 1991; Mineta et al., 1995; Andreanski et al., 1997), including those that can be activated by the different expression of protein in normal and cancer cells (Chase et al., 1998); and mutant adenoviruses that are unable to express the E1B55 kDa protein and are used to treat p53-mutant tumors (Bischof et al., 1996; Heise et al., 1997; Freytag et al., 1998; Kim et al., 1998). In all three systems, the goal is the intratumoral spread of the virus and the ability to selectively kill cancer cells. Genetically modified adenoviruses that target cellular pathways at key points have both potent and selective anti-cancer effects in gliomas. Frequently tested modifications of the adenovirus include deletion of the viral genes that interact with tumor suppressor genes, the modification of the tropism to infect cancer cells with more potency, and the inclusion in the viral genome of elements of transcription that are sensitive to transcription factors upregulated in cancer cells.
The role that preexisting immune conditions play and their influence in the overall clinical outcome of oncolytic virus therapy is presently unknown. The ability to accurately predict survival in patients treated with oncolytic viruses such as Delta-24-RGD would improve current treatment decisions. Furthermore, it would aid in the design of new therapies that may be tailored, with the basis of tumor properties and immune status. A significant advance in the field of biotherapy would occur because there is presently a dramatic lack of clinical biomarkers for cancer immunotherapy strategies.
The need for therapies effective against primary tumors of the nervous system, such as diffuse gliomas, anaplastic astrocytomas, anaplastic oligodendrogliomas, anaplastic mixed oligoastrocytoma, glioblastoma, ependymomas, and anaplastic ependymomas, or any primary brain tumor is particularly acute.